Numerous studies have demonstrated the importance of in vivo animal models in the study of mammalian organ systems, especially with respect to immune systems. Unfortunately, researchers studying the human immune system have been without such a model. Recently, several groups have reported the engraftment of human bone marrow cells or human fetal liver cells into mice exhibiting severe combined immunodeficiency (SCID). Lapidot et al., Science 255:1137 (1992); Mosier et al., Nature 335:256 (1988); McCune et al., Science 241:1632 (1988). Another report used immunodeficient bg/nu/xid mice to achieve similar results. Kamel-Reid et al., Science 242:1706 (1988). None of these studies was able to establish long-term proliferation and differentiation of human tissues in the host. Additionally, transient differentiation was achieved only by the addition of exogenous human growth factors. Lethally-irradiated mice have also been used as recipients for human bone marrow cells. Lubin et al., Science 252:427 (1991). This study also failed to produce continued, normal human cell differentiation.
Hematopoiesis is a hierarchial process involving cells at various stages of differentiation and development. In the murine system, it is well-established that hematopoietic stem cells are capable of reconstituting the hematopoietic system of lethally-irradiated recipients. Jones et al., Blood 73(2) :397 (1989). The most reliable assay for such activity is a transplantation assay demonstrating the reconstitution of primary and secondary recipients. Such an assay provides a valuable tool for the examination of the mouse immune system. However, because of the absence of a comparable model for humans, the understanding of human hematopoiesis is severely limited.
As mentioned above, there are reports of successful engraftment of human cells into immunodeficient mice. One of these studies, by Lapidot et al. (1992), used SCID mouse recipients for transplant of human bone marrow cells. When stimulated with combinations of erythropoietin (EPO) and human mast cell growth factor (hu-MGF), and/or PIXY321 (human IL-3 fusion protein), 76% of recipients showed engraftment of human cells in recipient bone marrow of 10 or more times that seen in animals receiving no growth factor treatment. Human tissue was of lymphoid, erythroid and myeloid character, indicating differentiation of transplanted tissue occurred. Without the addition of exogenous human growth factors, however, the relative amount of engraftment was low (0.01 to 1.0%). Moreover, it was unclear what effect extended discontinuation of growth factor treatment might have on subsequent stimulation. While this, and other previous studies represent important steps forward, they fall far short of a complete, functioning model of human hematopoiesis.
To date, however, no successful long-term engraftment, proliferation and differentiation of normal hematopoietic stem cells in a non-human mammal has been reported. As a result, no adequate animal model exists for the study of human hematopoiesis.